P.1.g.051 Benzodiazepine receptor system in the brains of rats with experimental alcoholism and treatment effect of a novel anticonvulsant

Abstract

Purpose: Alcohol abuse induces neuroadaptive alterations in the benzodiazepine receptors (BDR) that modulate GABAAR and GABA mediation in brain regions associated with reward function, producing alcohol addiction. Studying the effects of drugs that have modulatory effects on neuronal receptors, in particular the GABAA-benzodiazepine receptors, can be the basis for understanding the formation of alcohol motivation and addiction, to develop new approaches to the treatment of this disease. Materials and Methods: Male Wistar rats (n = 250) were used in an experimental model of alcoholism. Properties of BDR ‘synaptosomal’ and ‘mitochondrial’ types were examined in respective membrane fractions obtained from brain cortex of rats with experimental alcoholism and treatment with the novel anticonvulsant meta-chlorobenzhydryl urea by radioreceptor assay (RRA) with [3H]flunitrazepam and [3H]Ro5-4864. Results: Based on their consumption of 15% alcohol and/or water, the rats were divided into 3 major groups. Group 1 consisted of rats drinking ethanol only − these ‘heavy drinking’ rats had chronic alcoholism (15% alcohol as the sole source of drinking for 10 months); the second group consisted of rats preferring ethanol − these ‘non-heavy drinking’ rats drank mostly ethanol; the third group − ‘non-preferring’ rats − drank water mostly. In each group, a number of animals were administered meta-chlorobenzhydryl urea (m-CIBHU) 100mg/kg for 14 days. Introduction of m-CIBHU caused a significant decrease in alcohol consumption in animals preferring alcohol (1st and 2nd groups), by 82.7% from baseline and 75% from baseline, respectively (p< 0.05). Alcohol consumption by rats preferring water was not affected by m-CIBHU. Reduction of alcohol consumption started on the 2−3rd day of m-CIBHU administration, and persisted while on the drug and for 2 weeks after drug discontinuation. Thus, the introduction of m-CIBHU resulted in a significant reduction of ethanol intake for animals preferring ethanol. Comparative study of the kinetic parameters (Kd and Bmax) of [3H]flunitrazepam and [3H]Ro5-4864 binding with synaptosomal and mitochondrial membranes showed different properties of BDR in membranes from the brain cortex of rats with different preferences for alcohol: the affinity of [3H]flunitrazepam and [3H]Ro5-4864 binding with membranes was decreased, but capacity of receptors was increased, in the brain cortex of ‘heavy drinking’ and ‘non-heavy drinking’ rats compared with ‘non-preferring’ rats. Administration of the anticonvulsant meta-chlorobenzhydryl urea increased the affinity of BDR in the brain cortex of ‘heavy drinking’ rats, which induced mediation of GABA in the brain of these rats and reduced alcohol consumption. Conclusions: Our study revealed that the novel anticonvulsant meta-chlorobenzhydryl urea had a normalizing effect on GABAAreceptor function in ‘heavy drinking’ rats, and reduced alcohol consumption in these animals. P.1.g.052 Cariprazine demonstrates greater potency than aripiprazole in animal models of psychosis, cognitive impairment, and negative symptoms